Methods and Compositions for Treatment of Acute Lung Injury

ABSTRACT

A method of treating acute lung injury (ALI) in a patient suspected of having ALI is disclosed. The method includes administering to the patient a therapeutically effective amount of an inducible nitric oxide synthase (iNOS) inhibitor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 15/379,063 filedDec. 14, 2016, which claims benefit of U.S. Provisional PatentApplication 62/267,635, filed Dec. 15, 2015, which is incorporatedherein by reference as if set forth in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under U01ES017219awarded by the National Institutes of Health. The government has certainrights in the invention.

SEQUENCE LISTING

Not Applicable

BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention relates to treatments for acute lung injury (ALI).

2. Description of the Related Art

ALI is a common clinical syndrome characterized by lung alveolar injury,disruption of the alveolar capillary barrier, a neutrophilicinflammatory response, and marked pulmonary physical dysfunction asgassed by oxygenation, lung compliance, and airway resistance. ALI iscaused by a wide variety of insults including trauma, infection, sepsis,and inhalation or aspiration of toxic substances or chemicals.

In patients who develop ALI, the most common and sever manifestation isrespiratory failure. Insults leading to ALI cause disruption of thealveolar capillary barrier and alveolar injury. This results in leakageof fluid into the alveoli and marked thickening and inflammation of thealveolar walls. This, in turn, interferes with the ability of thealveoli to deliver inhaled oxygen to the blood. As a result, ALIpatients display sever hypoxemia, which can be observed as low bloodoxygen levels, which are often incompatible with normal tissue function.

The current state of the art treatment for ALI is supportive care. ALIpatients are typically placed on ventilator support in an ICU setting.In recent years, the only significant advances in the treatment of ALIrelate to the specifics of how this ventilator support is provided.There presently exists no pharmacologic agents that reduce the majorphysiologic cause of ALI, namely, disruption of the alveolar capillarybarrier, or that reduce the severity or mortality of ALI.

Inducible (or type 2) nitric oxide synthase (iNOS) is known to berelated to inflammation conditions. For example, Dugo et al. “Effects ofGW274150, a novel and selective inhibitor of iNOS activity, in acutelung inflammation”, British Journal of Pharmacology, 141, pp. 979-987(2004) reports that iNOS inhibitors can be effective in treating variousinflammatory diseases. However, no evidence has been presented nor hasit been hypothesized that this relation to inflammatory conditions wouldhave any implications for the treatment of ALI.

iNOS is also known to be related to the development of bleomycin-inducedlung injury. For example, Genovese et al. “Inhibition or knock out ofInducible nitric oxide synthase result in resistance tobleomycin-induced lung injury” Respiratory Research, 6:58 (2005) reportsthat iNOS plays a role in development of bleomycin-inducted lung injury.However, bleomycin-induced lung injury is a separate and distinctcondition from ALI and no evidence has been presented nor has it beenhypothesized that knowledge regarding the development and treatment ofbleomycin-induced lung injury is related to or predictive of developmentand treatment of ALI.

Accordingly, a need exists for methods and compositions for thetreatment of ALI, particularly for treatment of ALI resulting frominhalation of aspiration of toxic substances, such as chlorine.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides a method of treatingacute lung injury (ALI) in a patient suspected of having ALI. The methodcan include administering to the patient a therapeutically effectiveamount of an inducible nitric oxide synthase (iNOS) inhibitor.

In another aspect, the present disclosure provides a use of an iNOSinhibitor for treatment of ALI.

In yet another aspect, the present disclosure provides a method oftreating ALI in a patient suspected of having ALI. The method caninclude one or more of the following steps: measuring one or moreproperties in the patient; subsequently, administering to the patient atherapeutically effective amount of an iNOS inhibitor; and subsequently,monitoring the one or more properties in the patient. The one or moreproperties can be selected from the group consisting of: a ratio ofarterial oxygen partial pressure to fractional inspired oxygen(PaO₂/FiO₂ ratio) in the patient; an oxygenation index in the patient;an airway resistance in the patient; a peak inspiratory pressure in thepatient; a lung dynamic compliance in the patient; an oxygen saturationdrop in the patient; a mean airway pressure in the patient before; alung vascular leakage in the patient; and combinations thereof.

These and other features, aspects, and advantages of the presentinvention will become better understood upon consideration of thefollowing detailed description, drawings and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of Alveolar-arterial (A-a) O₂ gradient for theexperiments discussed in Example 1.

FIG. 2 is a plot of arterial oxygen partial pressure to fractionalinspired oxygen (PaO₂/FiO₂ ratio) for the experiments discussed inExample 1.

FIG. 3 is a plot of Oxygenation index for the experiments discussed inExample 1.

FIG. 4 is a plot of Airway Resistance for the experiments discussed inExample 1.

FIG. 5 is a plot of Peak Inspiratory Pressures for the experimentsdiscussed in Example 1.

FIG. 6 is a plot of Lung Dynamic Compliance for the experimentsdiscussed in Example 1.

FIG. 7 is a plot of O₂ Saturation for the experiments discussed inExample 1.

FIG. 8 is a plot of Mean Airway Pressure for the experiments discussedin Example 1.

FIG. 9 is a plot of lung vascular leakage for the experiments discussedin Example 1.

FIG. 10A is a plot of survival in chlorine-exposed rabbits in thepresence and absence of iNOS inhibition.

FIG. 10B is a plot of SpO2/FiO2 ratios over time in the rabbits thatsurvived 24 hours in FIG. 10A.

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is described in further detail, it is to beunderstood that the invention is not limited to the particularembodiments described. It is also to be understood that the terminologyused herein is for the purpose of describing particular embodimentsonly, and is not intended to be limiting. The scope of the presentinvention will be limited only by the claims. As used herein, thesingular forms “a”, “an”, and “the” include plural embodiments unlessthe context clearly dictates otherwise.

It should be apparent to those skilled in the art that many additionalmodifications beside those already described are possible withoutdeparting from the inventive concepts. In interpreting this disclosure,all terms should be interpreted in the broadest possible mannerconsistent with the context. Variations of the term “comprising” shouldbe interpreted as referring to elements, components, or steps in anon-exclusive manner, so the referenced elements, components, or stepsmay be combined with other elements, components, or steps that are notexpressly referenced. Embodiments referenced as “comprising” certainelements are also contemplated as “consisting essentially of” and“consisting of” those elements. In places where ranges of values aregiven, this disclosure explicitly contemplates other combinations of thelower and upper limits of those ranges that are not explicitly recited.For example, recitation of a value between 1 and 10 or between 2 and 9also contemplates a value between 1 and 9 or between 2 and 10. Rangesidentified as being “between” two values are inclusive of the end-pointvalues. For example, recitation of a value between 1 and 10 includes thevalues 1 and 10.

This disclosure relates generally to treatment of ALI. Specifically,this disclosure relates to methods and compositions for treatment of ALIresulting from toxic chemical inhalation.

This disclosure provides a method of treating ALI in a patient suspectedof having ALI. The method can include administering to the patient aniNOS inhibitor. The iNOS inhibitor can be administered in atherapeutically effective amount. In certain aspects, the iNOS inhibitorcan be (S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid (GW274150),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo [4,5-b]pyridine(BYK191023), the spiroquinazolone AR-C102222,[3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy]-2-phenylpyridine] (PPA250), and(N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-4-(methoxycarbonyl)-piperazine-2-acetamide(BBS-2).

ALI can be induced by a variety of causes. In certain aspects, the ALIcan be induced by inhalation or aspiration of a chemical irritant,pneumonia, sepsis, trauma, aspiration of gastric contents, bloodtransfusions, drug overdose, pancreatitis, burns, near drowning,pulmonary embolus, reperfusion injury, or a combination thereof.

ALI that is induced by inhalation or aspiration of a chemical irritantcan be inducted by a variety of chemical irritants. Examples of chemicalirritants that can induce ALI that is responsive to the methods andcompositions described herein include, but are not limited to, chlorinegas, smoke, phosgene, hydrochloric acid, Acrolein, Ammonia, Aniline,Arsenic trioxide, Arsine, Boron trifluoride, Cyanogen chloride, Hydrogenfluoride, Hydrogen sulfide, Methyl isocyanate, Phosphoro trichloride,Phosphorus trichloride, Sulfur dioxide, Sulfur trioxide, Chlorinedioxide, Bromine, Epichlorohydrin, Fluorine, Hydrazine, Hydrogenselenide, Methyl hydrazine, Benzenethiol, Dimethyl sulfate,Perfluoroisobutene, and combinations thereof.

The administering step can be performed in a variety of ways. In oneaspect, the administering can comprise orally administering, intravenousadministering, intramuscular administering, subcutaneous administering,administration via aerosol, or a combination thereof.

In aspects where the administering step includes orally administering,the methods can include orally administering the iNOS inhibitor in anamount between 0.01-6.0 mg/Kg, including but not limited to, an amountbetween 0.01-1.0 mg/Kg, between 1-2 mg/Kg, or between 2-6 mg/Kg.

The doses of the compositions or iNOS inhibitor may be provided as oneor several prepackaged units.

The terms “effective amount” or “therapeutically effective amount” referto an amount sufficient to effect beneficial or desirable biologicaland/or clinical results.

The duration of the treatment is usually once or twice per day for aperiod of time that will vary by subject, but will generally last untilthe condition is essentially controlled. In some embodiments, theduration of treatment may be multiple times per day, twice a day, oronce a day, and in some instances may be every other day or once a weekdepending on the state of the condition.

This disclosure also provides compositions that are tailored for use intreating ALI by way of oral administration. The compositions can includea pharmaceutically acceptable carrier and the iNOS inhibitor in anamount between 0.01-6.0 mg/Kg, including but not limited to, an amountbetween 0.01-1.0 mg/Kg, between 1-2 mg/Kg, or between 2-6 mg/Kg.Formulations suitable for oral administration include tablets bound withinert carriers and water-based oral solutions, among other formulationsunderstood by those having ordinary skill in the art to be suitable forthe oral administration described herein.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, the iNOS inhibitor isadmixed with at least one inert customary excipient (or carrier).Suitable inert customary excipients are known in the art, such as, forexample, but not limited to, sodium citrate or dicalcium phosphate or(a) fillers or extenders, as for example, starches, lactose, sucrose,mannitol, or silicic acid; (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, or acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, orsodium carbonate; (e) solution retarders, as for example, paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol or glycerolmonostearate; (h) adsorbents, as for example, kaolin or bentonite;and/or (i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules and tablets, the dosage forms may alsocomprise buffering agents.

A tablet comprising the active ingredient can, for example, be made bycompressing or molding the active ingredient, optionally with one ormore additional ingredients. Compressed tablets can be prepared bycompressing, in a suitable device, the active ingredient in afree-flowing form such as a powder or granular preparation, optionallymixed with one or more of a binder, a lubricant, an excipient, a surfaceactive agent, and a dispersing agent.

Tablets may be manufactured with pharmaceutically acceptable excipientssuch as inert diluents, granulating and disintegrating agents, bindingagents, and lubricating agents. Known dispersing agents include potatostarch and sodium starch glycolate. Known surface active agents includesodium lauryl sulfate. Known diluents include calcium carbonate, sodiumcarbonate, lactose, microcrystalline cellulose, calcium phosphate,calcium hydrogen phosphate, and sodium phosphate. Known granulating anddisintegrating agents include corn starch and alginic acid. Knownbinding agents include gelatin, acacia, pre-gelatinized maize starch,polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Knownlubricating agents include magnesium stearate, stearic acid, silica, andtalc.

Suitable liquid carrier(s) can be a solvent or dispersion mediumincluding, without limitation, water, ethanol, polyol (e.g., glycerol,propylene glycol, and liquid polyethylene glycol, and the like, or acombination thereof), one or more vegetable oils, or any combinationthereof, although additional pharmaceutically-acceptable components maybe included.

In aspects where the administering step includes intravenousadministering, the methods can include intravenous administering theiNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including but notlimited to, an amount between 0.01-1.0 mg/Kg, between 1-2 mg/Kg, orbetween 2-6 mg/Kg.

This disclosure also provides compositions that are tailored for use intreating ALI by way of intravenous administration. The compositions caninclude a pharmaceutically acceptable carrier and the iNOS inhibitor inan amount between 0.01-6.0 mg/Kg, including but not limited to, anamount between 0.01-1.0 mg/Kg, between 1-2 mg/Kg, or between 2-6 mg/Kgdissolved in normal saline or an analogous physiologic fluid.

In aspects where the administering step includes intramuscularadministering, the methods can include intramuscular administering theiNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including but notlimited to, an amount between 0.01-1.0 mg/Kg, between 1-2 mg/Kg, orbetween 2-6 mg/Kg.

This disclosure also provides compositions that are tailored for use intreating ALI by way of intramuscular administration. The compositionscan include a pharmaceutically acceptable carrier and the iNOS inhibitorin an amount between 0.01-6.0 mg/Kg, including but not limited to, anamount between 0.01-1.0 mg/Kg, between 1-2 mg/Kg, or between 2-6 mg/Kgdissolved in normal saline or an analogous physiologic fluid.

In one embodiment of the invention, the iNOS inhibitor or compositionsof the invention are administered directly to the lungs of the subjectby any suitable means, but are preferably administered by administeringan aerosol suspension of respirable particles comprised of the iNOSinhibitor, which the subject inhales. The iNOS inhibitor can beaerosolized in a variety of forms, such as, but not limited to, drypowder inhalants, metered dose inhalants, or liquid/liquid suspensions.The respirable particles may be liquid or solid.

In aspects where the administering step includes aerosol administering,the methods can include aerosol administering the iNOS inhibitor in anamount between 0.01-6.0 mg/Kg, including but not limited to, an amountbetween 0.01-1.0 mg/Kg, between 1-2 mg/Kg, or between 2-6 mg/Kg.

Solid or liquid particulate forms of the iNOS inhibitor prepared forpracticing the present invention should include particles of respirablesize: that is, particles of a size sufficiently small to pass throughthe mouth and larynx upon inhalation and into the bronchi and alveoli ofthe lungs of a subject. In general, particles ranging from about 1 to 10microns in size are within the respirable range. Particles ofnon-respirable size which are included in the aerosol tend to bedeposited in the throat and swallowed, and the quantity ofnon-respirable particles in the aerosol is preferably minimized. Theparticulate composition may optionally be combined with a carrier to aidin dispersion or transport. A suitable carrier such as a sugar (i.e.,lactose, sucrose, trehalose, mannitol) may be blended with the iNOSinhibitor(s) in any suitable ratio (e.g., a 1 to 1 ratio by weight).

Suitably, the compositions may be formulated into aerosols to beadministered by inhalation. Aerosols of liquid particles comprising theiNOS inhibitor may be produced by any suitable means, such as with apressure-driven aerosol nebulizer or an ultrasonic nebulizer. See, e.g.,U.S. Pat. No. 4,501,729, incorporated by reference in its entirety.

Nebulizers are commercially available devices known in the art whichtransform solutions or suspensions of the active ingredient into atherapeutic aerosol mist either by means of acceleration of compressedgas, typically air or oxygen, through a narrow orifice or by means ofultrasonic agitation. Several types of nebulizers are available,including, for example, jet nebulizers, ultrasonic nebulizers, vibratingmesh nebulizers.

Aerosols of solid particles comprising the iNOS inhibitor(s) maylikewise be produced with any solid particulate medication aerosolgenerator. Aerosol generators for administering solid particulatemedicaments to a subject are known in the art, for example, generate avolume of aerosol containing a predetermined metered dose of amedicament at a rate suitable for human administration. For example, asolid particulate aerosol generator may be, but not limited to, aninsufflator or a metered dose inhaler. Suitable compositions foradministration by insufflation include finely comminuted powders whichmay be delivered by means of an insufflator or taken into the nasalcavity in the manner of a snuff

The powder employed in the insufflator may consist either solely of theactive ingredient or of a powder blend comprising the active ingredient,a suitable powder diluent, such as lactose, and an optional surfactant.The iNOS inhibitor typically comprises from 0.1 to 100 w/w of thecomposition.

Suitable propellants include certain chlorofluorocarbon compounds, forexample, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane and mixtures thereof. The composition mayadditionally contain one or more co-solvents, for example, ethanol,surfactants, such as oleic acid or sorbitan trioleate, antioxidants andsuitable flavoring agents.

The method can further include measuring, monitoring, assessing, or inany other way determining one or more properties in the patient. Theseproperties can be measured prior to the administering and at varioustime points after the administering. The changes in the properties canbe an indication of the efficacy of the treatment. The one or moreproperties can be selected from the group consisting of: a ratio ofarterial oxygen partial pressure to fractional inspired oxygen(PaO₂/FiO₂ ratio) in the patient; an oxygenation index in the patient;an airway resistance in the patient; a peak inspiratory pressure in thepatient; a lung dynamic compliance in the patient; an oxygen saturationdrop in the patient; a mean airway pressure in the patient before; alung vascular leakage in the patient; other clinical measures ofrespiratory function; and combinations thereof.

The Alveolar−arterial gradient (A−aO₂ or A−a gradient), is a measure ofthe difference between the alveolar concentration (A) of oxygen and thearterial (a) concentration of oxygen. The equation for calculating theA−a gradient is: Aa Gradient=P_(A)O₂−P_(a)O₂, where P_(A)O₂=alveolar PO₂(calculated from the alveolar gas equation), P_(A)O₂=FiO₂(P_(atm)−P_(H2O))−P_(a)CO₂/0.8, where FiO₂=the fraction of inspiredoxygen, P_(H2O)=the partial pressure of water in the air,P_(a)CO₂=partial pressure of arterial carbon dioxide, measured directlyfrom a blood gas, and P_(a)O₂=arterial PO₂, measured directly from ablood gas.

The PaO₂/FiO₂ ratio is the ratio of arterial oxygen partial pressure,measured directly from a blood gas, to fractional inspired oxygen.

The oxygenation index is calculated using the formula oxygenationindex=(FiO₂×M_(Paw))/P_(a)O₂, where FiO₂=the fraction of inspiredoxygen, M_(Paw)=Mean airway pressure, and PaO₂=arterial PO₂, measureddirectly from a blood gas.

Mean airway pressure is the mean pressure applied duringpositive-pressure mechanical ventilation. This measurement is providedin real time by intensive care unit ventilators.

Airway resistance is the resistance of the respiratory tract to airflowduring inspiration and expiration. This measurement is provided in realtime by intensive care unit ventilators.

Peak inspiratory pressure is the highest level of pressure applied tothe lungs during the inhalation phase of mechanical ventilation. Thismeasurement is provided in real time by intensive care unit ventilators.

Lung compliance is a measure of the lung's ability to stretch andexpand. Dynamic compliance represents lung compliance during periods ofgas flow, such as during active inspiration. This measurement isprovided in real time by intensive care unit ventilators.

Oxygen saturation is a term referring to the fraction ofoxygen-saturated hemoglobin relative to total hemoglobin(unsaturated+saturated) in the blood. Oxygen saturation is measured inreal time using a pulse oximeter.

Lung vascular leakage is an inappropriate movement of fluid from theblood into the lung alveoli caused by injury to lung cells andmembranes. Lung vascular leakage can be measured by injecting a labeledhigh-molecular weight substance, such as FITC-Dextran, into the blood,waiting a short period of time, such a one hour, then sampling thecontents of the lung alveoli using bronchoalveolar lavage (BAL). A highconcentration of the labeled substance in the recovered BAL fluidsuggests increased lung vascular leakage.

EXAMPLE 1

The efficacy of an iNOS inhibitor in reducing ALI has been demonstratedin a preclinical model. In the model, ˜30 kg Yorkshire pigs (Sus scrofadomesticus) were sedated, intubated, placed on a ventilator, andinstrumented with arterial, pulmonary artery, and bladder catheters.Baseline hemodynamic, respiratory, and metabolic parameters wereobserved. The pigs were then exposed to 240 ppm chlorine gas via anendotracheal tube for 1 hour. After exposure, the pigs remained sedatedand ventilated and all measurements were repeated hourly until the endof the study. One hour after the end of chlorine exposure, pigs weretreated with either 200 mg of GW274150 or vehicle via intramuscularinjection. 22 hours after exposure, the pigs were injected intravenouslywith fluorescein isothiocyanate-dextran to measure lung vascularleakage. One hour later (23 hours after exposure), the pigs weresubjected to bronchoscopy and bronchoalveolar lavage (BAL). The pigswere then euthanized and lung tissues were obtained for patheologicanalysis. Pigs exposed to chlorine gas in this manner displayed allmajor features of human chlorine-induced ALI including histologicalevidence of tissue injury, alteration of the alveolar capillary barrier,a neutrophilic inflammatory response, and marked pulmonary physiologicaldysfunction.

Relative to vehicle treated pigs, pigs treated with GW274150 displayedimproved outcomes as illustrated in FIGS. 1-9. In FIGS. 1-8, the blackplot corresponds to pigs that were exposed to filtered air, the red plotcorresponds to pigs that were exposed to chlorine followed by placebo,and the blue plot corresponds to pigs that were exposed to chlorinefollowed by treatment with GW274150. Statistical significance wasdetermined by performing linear regression of all data points obtainedafter drug or placebo administration and comparing the slopes of theplacebo and GW274150 treatment groups. Dotted lines denote 99%confidence intervals.

As illustrated in FIG. 1, GW274150-treated pigs displayed a 55% decreasein the Alveolar−arterial (A−a) O₂ gradient on average 12-24 hours postexposure, when compared with vehicle-treated pigs. As illustrated inFIG. 2, GW274150-treated pigs displayed a 41% increase in a ratio ofarterial oxygen partial pressure to fractional inspired oxygen(PaO₂/FiO₂ ratio) on average 12-24 hours post exposure, when comparedwith vehicle-treated pigs. As illustrated in FIG. 3, GW274150-treatedpigs displayed a 60% decrease in Oxygenation index on average 12-24hours post exposure, when compared with vehicle-treated pigs. Asillustrated in FIG. 4, GW274150-treated pigs displayed a 69% decrease inAirway Resistance on average 12-24 hours post exposure, when comparedwith vehicle-treated pigs. As illustrated in FIG. 5, GW274150-treatedpigs displayed a 42% decrease in Peak Inspiratory Pressures on average12-24 hours post exposure, when compared with vehicle-treated pigs. Asillustrated in FIG. 6, GW274150-treated pigs displayed a 33% increase inLung Dynamic Compliance on average 12-24 hours post exposure, whencompared with vehicle-treated pigs. As illustrated in FIG. 7,GW274150-treated pigs displayed a 49% decrease in O₂ Saturation drop onaverage 12-24 hours post exposure, when compared with vehicle-treatedpigs. As illustrated in FIG. 8, GW274150-treated pigs displayed a 57%decrease in Mean Airway Pressure on average 12-24 hours post exposure,when compared with vehicle-treated pigs. As illustrated in FIG. 9,GW274150-treated pigs displayed a at 24 hours post exposure as measuredby FITC-dextran extravasion from blood to BAL fluid, when compared withvehicle-treated pigs.

The efficacy of a iNOS inhibitor in reducing chlorine-induced mortalityhas also been demonstrated in a preclinical model. In this model,rabbits are intubated, exposed to chlorine gas at the LD₅₀ dose (150 ppmfor 20 minutes), then extubated and followed for the next 24 hours.Rabbits were treated with vehicle or GW274150 1 hour after the end ofchlorine exposure.

As illustrated in FIG. 10A, GW274150-treated rabbits displayed completeprotection from chlorine-induced mortality. In addition, as illustratedin FIG. 10B, those vehicle-treated rabbits that survived displayedsignificantly more severe ALI, as measured by SpO2/FiO2 ratios, thanGW274150-treated rabbits.

These results demonstrated the efficacy of a iNOS inhibitor inattenuating the development of ALI in models that are representative ofchemical-induced ALI in humans. This attenuation of ALI is sufficient toprevent chlorine-induced mortality after what would otherwise be alethal dose of chlorine gas.

Although the invention has been described in considerable detail withreference to certain embodiments, one skilled in the art will appreciatethat the present invention can be practiced by other than the describedembodiments, which have been presented for purposes of illustration andnot of limitation. Therefore, the scope of the appended claims shouldnot be limited to the description of the embodiments contained herein.

What is claimed is:
 1. A method of treating acute lung injury (ALI) in apatient suspected of having ALI, the method comprising: administering tothe patient a therapeutically effective amount of an inducible nitricoxide synthase (iNOS) inhibitor.
 2. The method of claim 1, wherein theALI is induced by inhalation or aspiration of a chemical irritant. 3.The method of claim 2, wherein the chemical irritant is selected from agroup consisting of chlorine gas, smoke, phosgene, and combinationsthereof.
 4. The method of claim 1, wherein the administering comprisesorally administering, intravenous administering, intramuscularadministering or aerosol administering.
 5. The method of claim 4,wherein the administering comprises orally administering the iNOSinhibitor in an amount between 0.1 mg/Kg to 6.0 mg/Kg.
 6. The method ofclaim 4, wherein the administering comprises intravenous administeringthe iNOS inhibitor in an amount between 0.1 mg/Kg to 6.0 mg/Kg.
 7. Themethod of claim 4, wherein the administering comprises intramuscularadministering the iNOS inhibitor in an amount between 0.1 mg/Kg to 6.0mg/Kg.
 8. The method of claim 1, wherein the iNOS inhibitor is(S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid (GW274150).
 9. Themethod of claim 1, the method further comprising one or more of thefollowing steps: monitoring an alveolar-arterial oxygen gradient in thepatient before or after the administering; monitoring a ratio ofarterial oxygen partial pressure to fractional inspired oxygen(PaO₂/FiO₂ ratio) in the patient before or after the administering;monitoring an oxygenation index in the patient before or after theadministering; monitoring an airway resistance in the patient before orafter the administering; monitoring a peak inspiratory pressure in thepatient before or after the administering; monitoring a lung dynamiccompliance in the patient before or after the administering; monitoringan oxygen saturation drop in the patient before or after theadministering; monitoring a mean airway pressure in the patient beforeor after the administering; or monitoring a lung vascular leakage in thepatient before or after the administering.
 10. A method of treatingacute lung injury (ALI) in a patient suspected of having ALI, the methodcomprising: a) measuring one or more properties in the patient, the oneor more properties selected from the group consisting of: a ratio ofarterial oxygen partial pressure to fractional inspired oxygen(PaO₂/FiO₂ ratio) in the patient; an oxygenation index in the patient;an airway resistance in the patient; a peak inspiratory pressure in thepatient; a lung dynamic compliance in the patient; an oxygen saturationdrop in the patient; a mean airway pressure in the patient before; alung vascular leakage in the patient; and combinations thereof; b)subsequent to step a), administering to the patient a therapeuticallyeffective amount of an inducible nitric oxide synthase (iNOS) inhibitor;and c) subsequent to step b), monitoring the one or more properties inthe patient.
 11. The method of claim 10, wherein the ALI is induced byinhalation or aspiration of a chemical irritant.
 12. The method of claim11, wherein the chemical irritant is selected from a group consisting ofchlorine gas, smoke, phosgene, and combinations thereof.
 13. The methodof claim 10, wherein the administering comprises orally administering,intravenous administering, intramuscular administering or aerosoladministering.
 14. The method of claim 13, wherein the administeringcomprises orally administering the iNOS inhibitor in an amount between0.1 mg/Kg to 6.0 mg/Kg.
 15. The method of claim 10, wherein theadministering comprises intravenous administering.
 16. The method ofclaim 15, wherein the administering comprises intravenous administeringthe iNOS inhibitor in an amount between 0.1 mg/Kg to 6.0 mg/Kg.
 17. Themethod of claim 10, wherein the administering comprises intramuscularadministering.
 18. The method of claim 17, wherein the administeringcomprises intramuscular administering the iNOS inhibitor in an amountbetween 0.1 mg/Kg to 6.0 mg/Kg.
 19. The method of claim 10, wherein theiNOS inhibitor is (S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid(GW274150).